Investigations into derivatives of aspartic acid as non-nutritive sweeteners stem from the accidental discovery that L-aspartyl-L-phenylalanine methyl ester (Aspartame.RTM.) is sweet, 130-180 times sucrose, and free of unpleasant aftertaste. R. H. Mazur, J. M. Schlatter, and A. H. Goldkamp, JACS, 91, 2684 (1969). The authors disclosed that the L-aspartic acid portion of the molecule is critical for sweetness, but that considerable modification of the phenylalanine portion could be tolerated.
Subsequent work investigated the structural relationships of aspartic acid amides as regards sweetness. R. H. Mazur, A. H. Goldkamp, P. A. James, and J. M. Schlatter, J. Med. Chem., 13, 12-17 (1970). The authors' investigations attempted to delineate the structural requirements for good sweetness in alkyl amide derivatives of L-aspartic acid as revealed by tests of the following L-aspartate derivatives: ##STR1## R: 4-methylpentyl--tasteless
1-ethylbutyl--bitter PA1 hexyl--sweet, 1-2 X sucrose PA1 heptyl--sweet, 1-2 X sucrose PA1 1-methylbutyl--tasteless PA1 1-methylpentyl--sweet, 30 X sucrose PA1 1-methylhexyl--sweet, 20-50 X sucrose PA1 1-methylheptyl--sweet, 10 X sucrose PA1 1,3-dimethylbutyl--bitter PA1 1,3-dimethylpentyl--sweet, 1-2 X sucrose PA1 1,4-dimethylpentyl--sweet, 50-100 X sucrose
British Patent No. 1,381,826, Neely, Jan. 29, 1975, claims the use of L-aspartyl-L-1,4-dimethylpentylamide in oral compositions as a sweetener.
Y. Ariyoshi, N. Yasuda, K. Yamatani, Bull. Chem. Soc. Japan, 47, 326 (1974) describe investigations into the sweetness of hydroxy-substituted derivatives of L-aspartyl dipeptides. They report that both alpha-L-aspartyl-D-threo-threonine esters and alpha-L-aspartyl-D-erythro-threonine esters were sweet.
L-threonine derivatives of alpha-L-aspartic acid have no sweetness. L. B. P. Brussel, H. C. Peer, A. van der Heijden, Z. Lebensm. Unters. Forsch., 159, 339 (1975).
M. Miyoshi, K. Nanami, H. Sugano, T. Fujii, Bull. Chem. Soc. Japan, 51, 1433 (1978) disclose L-aspartyl dipeptides of the formula: ##STR2## as being sweet.
Belgian Patent No. 851,368, Ferrer, May 5, 1977, disclosed the L-aspartate of 6-amino-2-methyl-2-heptanol for use in the treatment of cardiac and pulmonary insufficiency.
In the gastrointestinal tract, L-aspartyl alkaneamides and L-aspartyl-1-hydroxymethyl alkaneamides are hydrolyzed to aspartic acid and the corresponding amine by aminopeptidase enzymes. E. F. Marsh, D. A. Herring, J. Pharm. Exp. Therapy, 102-178 (1951) describe a study of the comparative pharmacology of hydroxyl and methyl derivatives of 1,5-dimethylhexylamine (named as 6-methyl-2-heptylamine by the authors). These compounds would be produced by the hydrolysis of the L-aspartyl dimethylhexylamide. The data show the amine compound to have vasopressor and myocardial stimulant activity. This activity is shown to be lessened somewhat by 5-hydroxyl or 2- or 3-methyl substitution. 1,5-dimethylhexylamine has been sold commercially as a vasoconstrictor (Octodrine); 1,3-dimethyl pentylamine has been sold as a vasoconstrictor (Forthane); 1,5-dimethylaminohexan-5-ol hydrochloride has been sold as a cardiac stimulant and coronary vasodilator (Heptanol).